Abstract: Cancer is a complex disease characterized by the deregulation of normally balanced cell growth and survival pathways. Mutational alteration of specific oncogenes, such as PIK3CA and KRAS, can lead cancer cells to become dependent on their associated signaling pathways, a process known as oncogene addiction. As such, there has been a focused effort to develop inhibitors of major oncogenic pathways in cancer with the hypothesis that these drugs will cause tumor-specific cell death, ultimately leading to better outcomes in patients. However, intrinsic and acquired resistance to these so-called ?targeted therapies?, which is often driven by the activation of compensatory, or bypass, signaling mechanisms, limits their effectiveness by blocking drug- induced apoptosis (cell death). On the basis of these concepts, we hypothesized that we could improve the activity of targeted therapies by systematically identifying the pathways that drive resistance using high-throughput functional genomics approaches, coupled with mechanistic follow-up studies, and then leverage these insights to define combination therapies that drive potent and tumor-selective cell death. This project aims to characterize new dependencies, deemed ?collateral sensitivities?, in cancers that evolved resistance to a primary drug because these may be interesting therapeutic targets for patients that have already relapsed on a given targeted therapy. Collateral sensitivity is a concept that has been explored in detail in the microbial world. It is well established that once a bacterium becomes resistant to a given antibiotic, that bacterium often becomes hypersensitive to new antibiotics to which it was previously insensitive (collateral sensitivity). Reciprocally, that bacterium can also become resistant certain antibiotics to which it was previously sensitive (collateral resistance). There are many parallels between the fields of antibiotic resistance and resistance to targeted therapies in cancer; however, despite its potential clinical impact, there have not been any systematic efforts to study collateral sensitivity/resistance in diverse cancers.